Carbapenem antibacterial compounds, compositions containing such compounds and methods of treatment

ABSTRACT

The present invention relates to tricyclic carbapenem antibacterial agents in which the carbapenem nucleus is fused to a 6 membered carbocyclic ring. The compound is further substituted with various substituent groups including at least one cationic group.  
     The compounds are represented by formula I:  
                 
 
     Pharmaceutical compositions and methods of use are also included.

BACKGROUND OF THE INVENTION

[0001] The present invention relates to carbapenem antibacterial agentsin which the carbapenem nucleus is substituted at the 2-position with aiodophenoxy linked through a group —Z—CH₂—. Z represents antrans-ethenediyl or ethynediyl group. The iodophenoxy is furthersubstituted with various substituent groups including at least onecationic group.

[0002] The carbapenems of the present invention are useful against grampositive microorganisms, especially methicillin resistant Staphylococcusaureus (MRSA), methicillin resistant Staphylococcus epidermidis (MRSE),and methicillin resistant coagulase negative Staphylococci (MRCNS). Theantibacterial compounds of the present invention thus comprise animportant contribution to therapy for treating infections caused bythese difficult to control pathogens. There is an increasing need foragents effective against such pathogens (MRSA/MRCNS) which are at thesame time relatively free from undesirable side effects.

SUMMARY OF THE INVENTION

[0003] The present invention relates to anti-MRSA carbapenem antibioticscontaining aromatic based side-chains linked via an alkoxy unsaturatedgroup. The side-chain imparts MRS activity previously unassociated withthe carbapenem skeleton.

[0004] The compounds of the invention are represented by formula I:

[0005] or a pharmaceutically acceptable salt thereof, wherein:

[0006] R¹ represents H or methyl;

[0007] CO₂M represents a carboxylic acid, a carboxylate anion, apharmaceutically acceptable ester group or a carboxylic acid protectedby a protecting group;

[0008] X represents a halogen such as iodine, bromine, chlorine orfluorine;

[0009] P represents hydrogen, hydroxyl, F or hydroxyl protected by ahydroxyl-protecting group;

[0010] Z represents trans-ethenediyl or ethynediyl;

[0011] each R is independently selected from: —R*; —Q; hydrogen; halo;—CN; —NO₂; —NR^(a)R^(b); —OR^(c); —SR^(c); —C(O)NR^(a)R^(b);—C(O)OR^(h); —S(O)R^(c); —SO₂R^(c); —SO₂NR^(a)R^(b); —NR^(a)SO₂R^(b); —C(O)R^(a); —OC(O)R^(a); —OC(O)NR^(a)R^(b); —NR^(a)C(O)NR^(b)R^(c);—NR^(a)CO₂R^(h); —OCO₂R^(h); —NR^(a)C(O)R^(b); —C₁₋₆ straight- orbranched-chain alkyl, unsubstituted or substituted with one to fourR^(d) groups; and —C₃₋₇ cycloalkyl, unsubstituted or substituted withone to four R^(d) groups;

[0012] each R^(a), R^(b) and R^(c) independently represents hydrogen,—R*, —C₁₋₆ straight- or branched-chain alkyl, unsubstituted orsubstituted with one to four R^(d) groups, or —C₃₋₇ cycloalkyl,unsubstituted or substituted with one to four R^(d) groups;

[0013] or R^(a) and R^(b) taken together with any intervening atomsrepresent a 4-6 membered saturated ring optionally interrupted by one ormore of O, S, NR^(c), with R^(c) as defined above, or —C(O)—, said ringbeing unsubstituted or substituted with one to four R^(i) groups;

[0014] or R^(b) and R^(c) taken together with any intervening atomsrepresent a 4-6 membered saturated ring optionally interrupted by one tothree of O, S, NR^(a), with R^(a) as defined above, or —C(O)—, said ringbeing unsubstituted or substituted with one to four R^(i) groups;

[0015] each R^(d) independently represents halo; —CN; —NO₂;—NR^(e)R^(f); —OR^(g); —SR^(g); —CONR^(e)R^(f); —COOR^(g); —SOR^(g);—SO₂R^(g); —SO₂NR^(e)R^(f); —NR^(e)SO₂R^(f); —COR^(e); —NR^(e) COR^(f);—OCOR^(e); —OCONR^(e)R^(f); —NR^(e)CONR^(f)R^(g); —NR^(e)CO₂R^(h);—OCO₂R^(h); —C(NR^(e))NR^(f)R^(g); —NR^(e)C(NH)NR^(f)R^(g);—NR^(e)C(NR^(f))R^(g); —R* or —Q;

[0016] R^(e), R^(f) and R^(g) represent hydrogen; —R*; —C₁₋₆ straight-or branched-chain alkyl unsubstituted or substituted with one to fourR^(i) groups;

[0017] or R^(e) and R^(f) taken together with any intervening atomsrepresent a 4-6 membered saturated ring optionally interrupted by one tothree of O, S, —C(O)— or NR^(g) with R^(g) as defined above, said ringbeing unsubstituted or substituted with one to four R^(i) groups;

[0018] each R^(i) independently represents halo; —CN; —NO₂; phenyl;—NHSO₂R^(h); —OR^(h), —SR^(h); —N(R^(h))₂; —N⁺(R^(h))₃; — C(O)N(R^(h))₂;—SO₂N(R^(h))₂; heteroaryl; heteroarylium; —CO₂R^(h); —C(O)R^(h);—OCOR^(h); —NHCOR^(h); guanidinyl; carbamimidoyl or ureido;

[0019] each R^(h) independently represents hydrogen, a —C₁₋₆ straight orbranched-chain alkyl group, a —C₃-C₆ cycloalkyl group or phenyl, or whentwo R^(h) groups are present, said R^(h) groups may be taken incombination and represent a 4-6 membered saturated ring, optionallyinterrupted by one or two of O, S, SO₂, —C(O)—, NH and NCH₃;

[0020] Q is selected from the group consisting of:

[0021] wherein:

[0022] a and b are 1, 2 or 3;

[0023] L— is a pharmaceutically acceptable counterion;

[0024] α represents O, S or NR^(s);

[0025] β, δ, λ, μ and σ represent CR^(t), N or N⁺R^(s), provided that nomore than one of β, δ, λ, μ and σ is N⁺R^(s);

[0026] R* is selected from the group consisting of:

[0027] wherein:

[0028] d represents O, S or NR^(k);

[0029] e, g, x, y and z represent CR^(m), N or N⁺R^(k), provided that nomore than one of e, g, x, y and z in any given structure representsN⁺R^(k);

[0030] R^(k) represents hydrogen; —C₁₋₆ straight- or branched-chainalkyl, unsubstituted or substituted with one to four R^(i) groups; or—(CH₂)_(n)Q where n=1, 2 or 3 and Q is as previously defined;

[0031] each R^(m) independently represents a member selected from thegroup consisting of: hydrogen; halo; —CN; —NO₂; —NR^(n)R^(o); —OR^(n);—SR^(n); —CONR^(n)R^(o); —COOR^(h); —SOR^(n); —SO₂R^(n);—SO₂NR^(n)R^(o); — NR^(n)SO₂R^(o); —COR^(n); —NR^(n)COR^(o); —OCOR^(n);—OCONR^(n)R^(o); —NR^(n)CO₂R^(h); — NR^(n)CONR^(o)R^(h); —OCO₂R^(h);—CNR^(n)NR^(o)R^(h); —NR^(n)CNHNR^(o)R^(h); —NR^(n)C(NR^(o))R^(h); —C₁₋₆ straight- or branched-chain alkyl, unsubstituted or substitutedwith one to four R^(i) groups; —C₃₋₇ cycloalkyl, unsubstituted orsubstituted with one to four R^(i) groups; and —(CH₂)_(n)Q where n and Qare as defined above;

[0032] R^(n) and R^(o) represent hydrogen, phenyl; —C₁₋₆ straight- orbranched-chain alkyl unsubstituted or substituted with one to four R^(i)groups;

[0033] each R^(s) independently represents hydrogen; phenyl or —C₁₋₆straight- or branched-chain alkyl, unsubstituted or substituted with oneto four R^(i) groups;

[0034] each R^(t) independently represents hydrogen; halo; phenyl; —CN;—NO₂; —NR^(u)R^(v); —OR^(u); —SR^(u); —CONR^(u)R^(v); —COOR^(h);—SOR^(u); —SO₂R^(u); —SO₂NR^(u)R^(v); —NR^(u)SO₂R^(v); —COR^(u);—NR^(u)COR^(v); —OCOR^(u); — OCONR^(u)R^(v); —NR^(u)CO₂R^(v);—NR^(u)CONR^(v)R^(w); —OCO₂R^(v); —C₁₋₆ straight- or branched-chainalkyl, unsubstituted or substituted with one to four R^(i) groups;

[0035] R^(u) and R^(v) represent hydrogen or —C₁₋₆ straight- orbranched-chain alkyl, unsubstituted or substituted with one to fourR^(i) groups;

[0036] or R^(u) and R^(v) together with any intervening atoms representa 4-6 membered saturated ring optionally interrupted by one or more ofO, S, NR^(w) or —C(O)—, said ring being unsubstituted or substitutedwith one to four R^(i) groups;

[0037] each R^(w) independently represents hydrogen; —C₁₋₆ straight- orbranched-chain alkyl, unsubstituted or substituted with one to fourR^(i) groups; C₃₋₆ cycloalkyl optionally substituted with one to fourR^(i) groups; phenyl optionally substituted with one to four R^(i)groups, or heteroaryl optionally substituted with 1-4 R^(i) groups;

[0038] or R^(h) and R^(w) taken together with any intervening atomsrepresent a 5-6 membered saturated ring, optionally interrupted by oneor two of O, S, SO₂, NH or NCH₃;

[0039] R^(x) represents hydrogen or a C₁₋₈ straight- or branched-chainalkyl, optionally interrupted by one or two of O, S, SO, SO₂, NR^(w),N⁺R^(h)R^(w), or —C(O)—, said chain being unsubstituted or substitutedwith one to four of halo, CN, NO₂, OR^(w), SR^(w), SOR^(w), SO₂R^(w),NR^(h)R^(w), N⁺(R^(h))₂R^(w), —C(O)—R^(w), C(O)NR^(h)R^(w),SO₂NR^(h)R^(w), CO₂R^(w), OC(O)R^(w), OC(O)NR^(h)R^(w), NR^(h)C(O)R^(w),NR^(h)C(O)NR^(h)R^(w), or a phenyl or heteroaryl group which is in turnoptionally substituted with from one to four R^(i) groups or with one totwo C₁₋₃ straight- or branched-chain alkyl groups, said alkyl groupsbeing unsubstituted or substituted with one to four R^(i) groups;

[0040] R^(y) and R^(z) represent hydrogen; phenyl; —C₁₋₆ straight orbranched chain alkyl, unsubstituted or substituted with one to fourR^(i) groups, and optionally interrupted by O, S, NR^(w), N⁺R^(h)R^(w)or —C(O)—;

[0041] or R^(x) and R^(y) together with any intervening atoms representa 4-6 membered saturated ring optionally interrupted by O, S, SO₂,NR^(w), N⁺R^(h)R^(w) or —C(O)—, unsubstituted or substituted with 1-4R^(i) groups,

[0042] and when R^(x) and R^(y) together represent a 4-6 membered ringas defined above, R^(z) is as defined above or R^(z) represents anadditional saturated 4-6 membered ring fused to the ring represented byR^(x) and R^(y) taken together, optionally interrupted by O, S, NR^(w)or —C(O)—, said rings being unsubstituted or substituted with one tofour R^(i) groups.

[0043] Pharmaceutical compositions and methods of treatment are alsoincluded herein.

DETAILED DESCRIPTION OF THE INVENTION

[0044] The invention is described herein in detail using the termsdefined below unless otherwise specified.

[0045] Carboxylate anion refers to a negatively charged group —COO—.

[0046] The term “alkyl” refers to a monovalent alkane (hydrocarbon)derived radical containing from 1 to 10 carbon atoms unless otherwisedefined. It may be straight, branched or cyclic. Preferred alkyl groupsinclude methyl, ethyl, propyl, isopropyl, butyl, t-butyl, cyclopentyland cyclohexyl. When substituted, alkyl groups may be substituted withup to four substituent groups, selected from R^(d) and R^(i), asdefined, at any available point of attachment. When the alkyl group issaid to be substituted with an alkyl group, this is used interchangeablywith “branched alkyl group”.

[0047] Cycloalkyl is a specie of alkyl containing from 3 to 15 carbonatoms, without alternating or resonating double bonds between carbonatoms. It may contain from 1 to 4 rings which are fused.

[0048] The term “alkenyl” refers to a hydrocarbon radical, straight,branched or cyclic containing from 2 to 10 carbon atoms and at least onecarbon to carbon double bond. Preferred alkenyl groups include ethenyl,propenyl, butenyl and cyclohexenyl.

[0049] The term “alkynyl” refers to a hydrocarbon radical, straight orbranched, containing from 2 to 10 carbon atoms and at least one carbonto carbon triple bond. Preferred alkynyl groups include ethynyl,propynyl and butynyl.

[0050] Aryl refers to aromatic rings e.g., phenyl, substituted phenyland the like, as well as rings which are fused, e.g., naphthyl,phenanthrenyl and the like. An aryl group thus contains at least onering having at least 6 atoms, with up to five such rings being present,containing up to 22 atoms therein, with alternating (resonating) doublebonds between adjacent carbon atoms or suitable heteroatoms. Thepreferred aryl groups are phenyl, naphthyl and phenanthrenyl. Arylgroups may likewise be substituted as defined. Preferred substitutedaryls include phenyl and naphthyl.

[0051] The term “heteroaryl” refers to a monocyclic aromatic hydrocarbongroup having 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to10 atoms, containing at least one heteroatom, O, S or N, in which acarbon or nitrogen atom is the point of attachment, and in which one ortwo additional carbon atoms is optionally replaced by a heteroatomselected from O or S, and in which from 1 to 3 additional carbon atomsare optionally replaced by nitrogen heteroatoms, said heteroaryl groupbeing optionally substituted as described herein. Examples of this typeare pyrrole, pyridine, oxazole, thiazole and oxazine. Additionalnitrogen atoms may be present together with the first nitrogen andoxygen or sulfur, giving, e.g., thiadiazole. Examples include thefollowing:

[0052] Heteroarylium refers to heteroaryl groups bearing a quaternarynitrogen atom and thus a positive charge. Examples include thefollowing:

[0053] When a charge is shown on a particular nitrogen atom in a ringwhich contains one or more additional nitrogen atoms, it is understoodthat the charge may reside on a different nitrogen atom in the ring byvirtue of charge resonance that occurs.

[0054] The term “heterocycloalkyl” refers to a cycloalkyl group(nonaromatic) in which one of the carbon atoms in the ring is replacedby a heteroatom selected from O, S or N, and in which up to threeadditional carbon atoms may be replaced by hetero atoms.

[0055] The terms “quaternary nitrogen” and “positive charge” refer totetravalent, positively charged nitrogen atoms including, e.g., thepositively charged nitrogen in a tetraalkylammonium group (e. g.tetramethylammonium), heteroarylium, (e.g., N-methylpyridinium), basicnitrogens which are protonated at physiological pH, and the like.Cationic groups thus encompass positively charged nitrogen-containinggroups, as well as basic nitrogens which are protonated at physiologicpH.

[0056] The term “heteroatom” means O, S or N, selected on an independentbasis.

[0057] Halogen and “halo” refer to bromine, chlorine, fluorine andiodine.

[0058] Alkoxy refers to C₁-C₄ alkyl-O—, with the alkyl group optionallysubstituted as described herein.

[0059] When a group is termed “substituted”, unless otherwise indicated,this means that the group contains from 1 to 4 substituents thereon.With respect to R, R^(a), R^(b) and R^(c), the substituents available onalkyl groups are selected from the values of R^(d). Many of the variablegroups are optionally substituted with up to four R^(i) groups. Withrespect to R^(e), R^(f) and R^(g), when these variables representsubstituted alkyl, the substituents available thereon are selected fromthe values of R^(i).

[0060] When a functional group is termed “protected”, this means thatthe group is in modified form to preclude undesired side reactions atthe protected site. Suitable protecting groups for the compounds of thepresent invention will be recognized from the present application takinginto account the level of skill in the art, and with reference tostandard textbooks, such as Greene, T. W. et al. Protective Groups inOrganic Synthesis Wiley, New York (1991).

[0061] Examples of suitable protecting groups are contained throughoutthe specification.

[0062] When an alkyl group is “interrupted by” 1 or more moieties, suchas O, S, N, —C(O)— and the like, this includes alkyl groups which areterminated by the moiety or moieties, as well as alkyl groups that areinterrupted or terminated by combinatios of such groups. Thus forexample, —C(O)O—, —OC(O)—, —C(O)NR⁸— and similar such moieties areincluded. Examples of alkyl groups terminated by the moiety or moietiesare as follows: —O—C₁₋₆ alkyl, —C₁₋₆ alkyl-O—, —C₁₋₆ alkyl-OC(O)—,—O—C₁₋₆ alkyl-S— and the like. Obviously other moieties are included inaccordance with the general description contained herein.

[0063] In some of the carbapenem compounds of the present invention, Mis a readily removable carboxyl protecting group, and/or P represents ahydroxyl which is protected by a hydroxyl-protecting group. Suchconventional protecting groups consist of known groups which are used toprotectively block the hydroxyl or carboxyl group during the synthesisprocedures described herein. These conventional blocking groups arereadily removable, i.e., they can be removed, if desired, by procedureswhich will not cause cleavage or other disruption of the remainingportions of the molecule. Such procedures include chemical and enzymatichydrolysis, treatment with chemical reducing or oxidizing agents undermild conditions, treatment with a transition metal catalyst and anucleophile and catalytic hydrogenation.

[0064] Examples of carboxyl protecting groups include allyl, benzhydryl,2-naphthylmethyl, benzyl, silyl such as t-butyldimethylsilyl (TBS),phenacyl, p-methoxybenzyl, o-nitrobenzyl, p-methoxyphenyl,p-nitrobenzyl, 4-pyridylmethyl and t-butyl.

[0065] Examples of suitable hydroxyl protecting groups includetriethylsilyl (TES), t-butyldimethylsilyl (TBS), t-butyldiphenylsilyl(DPTBS), o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl,benzyloxycarbonyl, allyloxycarbonyl, t-butyloxycarbonyl,2,2,2-trichloroethyloxycarbonyl and the like.

[0066] The carbapenem compounds of the present invention are useful perse and in their pharmaceutically acceptable salt and ester forms for thetreatment of bacterial infections in animal and human subjects. The term“pharmaceutically acceptable ester, salt or hydrate,” refers to thosesalts, esters and hydrated forms of the compounds of the presentinvention which would be apparent to the pharmaceutical chemist. i.e.,those which are substantially non-toxic and which may favorably affectthe pharmacokinetic properties of said compounds, such as palatability,absorption, distribution, metabolism and excretion. Other factors, morepractical in nature, which are also important in the selection, are costof the raw materials, ease of crystallization, yield, stability,solubility, hygroscopicity and flowability of the resulting bulk drug.Conveniently, pharmaceutical compositions may be prepared from theactive ingredients in combination with pharmaceutically acceptablecarriers. Thus, the present invention is also concerned withpharmaceutical compositions and methods of treating bacterial infectionsutilizing as an active ingredient the novel carbapenem compounds.

[0067] With respect to —CO₂M, which is attached to the carbapenemnucleus at position 3, this represents a carboxylic acid group (Mrepresents H), a carboxylate anion (M represents a negative charge), apharmaceutically acceptable ester (M represents an ester forming group)or a carboxylic acid protected by a protecting group (M represents acarboxyl protecting group). The pharmaceutically acceptable saltsreferred to above may take the form —COOM, where M is a negative charge,which is balanced by a counterion, e.g., an alkali metal cation such assodium or potassium. Other pharmaceutically acceptable counterions maybe calcium, magnesium, zinc, ammonium, or alkylammonium cations such astetramethylammonium, tetrabutylammonium, choline, triethylhydroammonium,meglumine, triethanolhydroammonium, etc.

[0068] The pharmaceutically acceptable salts referred to above alsoinclude acid addition salts. Thus, the Formula I compounds can be usedin the form of salts derived from inorganic or organic acids. Includedamong such salts are the following: acetate, adipate, alginate,aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate,camphorate, camphorsulfonate, cyclopentanepropionate, digluconate,dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate,glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate.

[0069] The pharmaceutically acceptable esters are such as would bereadily apparent to a medicinal chemist, and include, for example, thosedescribed in detail in U.S. Pat. No. 4,309,438. Included within suchpharmaceutically acceptable esters are those which are hydrolyzed underphysiological conditions, such as pivaloyloxymethyl, acetoxymethyl,phthalidyl, indanyl and methoxymethyl, and others described in detail inU.S. Pat. No. 4,479,947. These are also referred to as “biolabileesters”.

[0070] Biolabile esters are biologically hydrolizable, and may besuitable for oral administration, due to good absorption through thestomach or intenstinal mucosa, resistance to gastric acid degradationand other factors. Examples of biolabile esters include compounds inwhich M represents an alkoxyalkyl, alkylcarbonyloxyalkyl,alkoxycarbonyloxyalkyl, cycloalkoxyalkyl, alkenyloxyalkyl, aryloxyalkyl,alkoxyaryl, alkylthioalkyl, cycloalkylthioalkyl, alkenylthioalkyl,arylthioalkyl or alkylthioaryl group. These groups can be substituted inthe alkyl or aryl portions thereof with acyl or halo groups. Thefollowing M species are examples of biolabile ester forming moieties.:acetoxymethyl, 1-acetoxyethyl, 1-acetoxypropyl, pivaloyloxymethyl,1-isopropyloxycarbonyloxyethyl, 1-cyclohexyloxycarbonyloxyethyl,phthalidyl and (2-oxo-5-methyl-1,3-dioxolen-4-yl)methyl.

[0071] L— can be present or absent as necessary to maintain theappropriate charge balance. When present, L— represents apharmaceutically acceptable counterion. Most anions derived frominorganic or organic acids are suitable. Representative examples of suchcounterions are the following: acetate, adipate, aminosalicylate,anhydromethylenecitrate, ascorbate, aspartate, benzoate,benzenesulfonate, bromide, citrate, camphorate, camphorsulfonate,chloride, estolate, ethanesulfonate, fumarate, glucoheptanoate,gluconate, glutamate, lactobionate, malate, maleate, mandelate,methanesulfonate, pantothenate, pectinate, phosphate/diphosphate,polygalacturonate, propionate, salicylate, stearate, succinate, sulfate,tartrate and tosylate. Other suitable anionic species will be apparentto the ordinarily skilled chemist.

[0072] Likewise, when L— represents a specie with more than one negativecharge, such as malonate, tartrate or ethylenediamine-tetraacetate(EDTA), an appropriate number of carbapenem molecules can be found inassociation therewith to maintain the overall charge balance andneutrality.

[0073] At least one of the R groups attached to the phenoxy platform canoptionally contain a positively charged moiety. Thus, it can include —R*or Q, or a moiety which in turn contains a positively charged group.

[0074] A subset of compounds of formula I which is of interest relatesto those compounds where CO₂M represents a carboxylate anion. Hence, Min this instance represents a negative charge which will be balanced bya positively charged group, such as in the positively charged R group.Likewise, if the positively charged R group contains more than onepositive charge, a negatively charged counterion may be present which incombination with the carboxylate anion, provides overall chargeneutrality.

[0075] Another subset of compounds of formula I which is of interestrelates to compounds wherein one R represents a group which contains apositively charged moiety, and the remaining R groups are selected fromhydrogen and C₁₋₆ straight or branched chain alkyl, unsubstituted orsubstituted with one to four R^(d) groups. More particularly, thissubset of interest includes compounds of formula Ia wherein one Rrepresents a group containing a positively charged moiety and theremaining R groups are hydrogen.

[0076] With respect to the positively charged moiety or moieties thatare contained in one or more R groups, it is preferred that from 1-3positive charges be present, and most preferably one positive charge bepresent, balanced by the carboxylate anion and a negatively chargedcounterion.

[0077] Another subset of compounds which is of interest is representedby formula I wherein one R group represents a —C₁₋₆ straight or branchedchain alkyl group, substituted with one to four R^(d) groups, whereinone R^(d) group represents —R* or Q. Hence, a positively charged moiety—R* or Q is attached to an alkyl group.

[0078] Another subset of compounds which is of interest is representedby formula I wherein one R group represents a group without a positivelycharged moiety.

[0079] Another group of compounds of interest is represented by formulaI wherein Q is selected from the group consisting of:

[0080] More particularly, the group of compounds which is of interest isrepresented by formula I wherein Q represents:

[0081] Within this subset of compounds, L—, a and b are as originallydefined, and R^(x) is as originally defined, and represents a memberselected from the group consisting of: hydrogen or a C₁₋₈ straight- orbranched-chain alkyl, optionally interrupted or terminated by one or twoof O, S, SO, SO₂, NR^(w), N⁺R^(h)R^(w), or —C(O)—, said chain beingunsubstituted or substituted with one to four of halo, CN, NO₂, OR^(w),SR^(w), SOR^(w), SO₂R^(w), NR^(h)R^(w), N⁺(R^(h))₂R^(w), —C(O)—R^(w),C(O)NR^(h)R^(w), SO₂NR^(h)R^(w), CO₂R^(w), OC(O)R^(w), OC(O)NR^(h)R^(w),NR^(h)C(O)R^(w), NR^(h)C(O)NR^(h)R^(w), or a phenyl or heteroaryl groupwhich is in turn optionally substituted with from one to four R^(i)groups or with one to two C₁₋₃ straight- or branched-chain alkyl groups,said alkyl groups being unsubstituted or substituted with one to fourR^(i) groups.

[0082] Another group of compounds of interest is represented by formulaI wherein Q represents —N⁺R^(x)R^(y)R^(z), wherein R^(x), R^(y) andR^(z) are as originally defined.

[0083] Another group of compounds of interest is represented by formulaI wherein one R* group is present and is selected from:

[0084] Within this subset, d represents NR^(k); R^(k) represents —C₁₋₆straight or branched chain alkyl; and e, g, x and y represent CR^(m) orN⁺R^(k), with R^(k) as defined above and R^(m) representing hydrogen.

[0085] Another group of compounds of interest is represented by formulaI wherein R is A—(CH₂)_(n)—Q, wherein A is O, S or CH₂, n is 0-3 and Qis as originally defined.

[0086] Another group of compounds of interest is represented by formulaI wherein Z is trans-CH═CH and all other variables are as originallydescribed.

[0087] Another group of compounds of interest is represented by formulaI wherein X is iodine and all other variables are as originallydescribed.

[0088] Another group of compounds of interest is represented by formulaI wherein Z is —C≡C— and all other variables are as originallydescribed.

[0089] A preferred subset of compounds of formula I which is ofparticular interest relates to compounds represented by formula Ia

[0090] wherein:

[0091] Z is as originally described;

[0092] CO₂M represents a carboxylate anion;

[0093] R group contains a positively charged moiety;

[0094] Rd is as originally defined;

[0095] R^(h) represents hydrogen or a C₁₋₆ straight or branched chainalkyl group;

[0096] Q is selected from the group consisting of:

[0097] wherein L—, a and b are as originally defined, and R^(x)represents a member selected from the group consisting of: hydrogen or aC₁₋₈ straight- or branched-chain alkyl, optionally interrupted orterminated by one or two of O, S, SO, SO₂, NR^(w), N⁺R^(h)R^(w), or—C(O)—, said chain being unsubstituted or substituted with one to fourof halo, CN, NO₂, OR^(w), SR^(w), SOR^(w), SO₂R^(w), NR^(h)R^(w),N⁺(R^(h))₂R^(w), —C(O)—R^(w), C(O)NR^(h)R^(w), SO₂NR^(h)R^(w), CO₂R^(w),OC(O)R^(w), OC(O)NR^(h)R^(w), NR^(h)C(O)R^(w), NR^(h)C(O)NR^(h)R^(w),phenyl or heteroaryl, said phenyl or heteroaryl group being optionallysubstituted with from one to four R^(i) groups or with one to two C₁₋₃straight- or branched-chain alkyl groups, said alkyl groups beingunsubstituted or substituted with one to four R^(i) groups;

[0098] R* is selected from:

[0099] wherein d represents NR^(k); R^(k) represents —C₁₋₆ straight orbranched chain alkyl; and e, g, x and y represent CR^(m) or N⁺R^(k),with R^(k) as defined above and R^(m) representing hydrogen.

[0100] Within this subset, all other variables are as originally definedwith respect to formula I.

[0101] Another preferred subset of compounds of formula Ia is realizedwhen G is 1, 3-4, 6, 8, 9 or 10, wherein R contains a positively chargedmoiety selected from the group consisting of: —R*, Q, A—(CH₂)_(n)—Q, anda C₁₋₆ straight or branched alkyl chain substituted with one R^(d)group, wherein A is as originally described

[0102] R^(d) is independently selected —R* or Q;

[0103] Q is selected from the group consisting of:

[0104] wherein L—, a and b are as originally defined, and R^(x)represents a member selected from the group consisting of: hydrogen or aC₁₋₈ straight- or branched-chain alkyl, optionally interrupted by one ortwo of O, S, SO, SO₂, NR^(w), N⁺R^(h)R^(w), or —C(O)—, said chain beingunsubstituted or substituted with one to four of halo, CN, NO₂, OR^(w),SR^(w), SOR^(w), SO₂R^(w), NR^(h)R^(w), N⁺(R^(h))₂R^(w), —C(O)—R^(w),C(O)NR^(h)R^(w), SO₂NR^(h)R^(w), CO₂R^(w), OC(O)R^(w), OC(O)NR^(h)R^(w),NR^(h)C(O)R^(w), NR^(h)C(O)NR^(h)R^(w), phenyl or heteroaryl, saidphenyl and heteroaryl group being optionally substituted with from oneto four R^(i) groups or with one to two C₁₋₃ straight or branched chainalkyl groups, said alkyl groups being unsubstituted or substituted withone to four R^(i) groups;

[0105] R* is selected from:

[0106] wherein d represents NR^(k); R^(k) represents —C₁₋₆ straight orbranched chain alkyl; and e, g, x and y represent CR^(m) or N⁺R^(k),with R^(k) as defined above and R^(m) representing hydrogen.

[0107] An even more preferred subset of formula Ia is realized when G is8 or 9.

[0108] Another preferred subset of compounds is represented by formulaIb:

[0109] or a pharmaceutically acceptable salt thereof, wherein:

[0110] Z is as originally described;

[0111] CO₂M represents a carboxylate anion;

[0112] Within this subset, all other variables are as originally definedwith respect to formula I.

[0113] Another more preferred subset of compounds of the invention isrepresented by formula Ic:

[0114] wherein:

[0115] R represents

[0116] and R^(x), a, b and L— are as originally defined.

[0117] Another more preferred subset of the compounds of formula Id isrealized when:

[0118] R represents A—(CH₂)_(n)—Q, wherein A is 0, S or CH₂, n is 0-3and Q is selected from the group consisting of:

[0119] wherein L—, a and b are as originally defined, and R^(x)represents a member selected from the group consisting of: hydrogen or aC₁₋₈ straight- or branched-chain alkyl, optionally interrupted by one ortwo of O, S, SO, SO₂, NR^(w), N⁺R^(h)R^(w), or —C(O)—, said chain beingunsubstituted or substituted with one to four of halo, CN, NO₂, OR^(w),SR^(w), SOR^(w), SO₂R^(w), NR^(h)R^(w), N⁺(R^(h))₂R^(w), —C(O)—R^(w),C(O)NR^(h)R^(w), SO₂NR^(h)R^(w), CO₂R^(w), OC(O)R^(w), OC(O)NR^(h)R^(w),NR^(h)C(O)R^(w), NR^(h)C(O)NR^(h)R^(w), phenyl or heteroaryl, saidphenyl and heteroaryl group being optionally substituted with from oneto four R^(i) groups or with one to two C₁₋₃ straight or branched chainalkyl groups, said alkyl groups being unsubstituted or substituted withone to four R^(i) groups.

[0120] Within the subsets, all other variables are as originally definedwith respect to formula I.

[0121] Representative examples of compounds of the invention are shownbelow. The invention is intended, where appropriate, to includeprotonated amines protonated at the appropriate pH, e.g., pH 7.

[0122] or the pharmaceutically acceptable salts thereof.

[0123] The compounds of the present invention are prepared by two basicprocesses which are illustrated by the following generic schemes:

[0124] The compounds of the present invention are prepared as depictedin Flow sheets A and B. The vinyl linked carbapenems are prepared, asshown in Flow sheet A, by reacting a suitably protected, activated2-triflyl-carbapen-2-em-3-carboxylate A1 with a hydroxy allylic trialkylstannane, to produce A2, and then reacting the iodophenoxy underMitsunobu conditions to produce A3. Removing any protecting groups whichare present affords the desired final vinyllic product A4.

[0125] The acetylenic linked carbapenems are prepared as shown in Flowsheet B in which intermediate A1 is reacted with a protected hydroxypropargylic trialkyl stannane to produce A5, deprotecting thepropargylic hydroxy group to produce A6, and then reacting theiodophenoxy under Mitsunobu conditions to produce A7. Removing anyprotecting groups which are present affords the desired final acetylenicproduct A8.

[0126] Flow Sheet C describes the synthesis of the condensed biarylcarbapenem that possess a charged group Q, as previously defined.Typically, the intermediates A3 and A7 from Flow Sheets A and B possessan R group, as previously defined, which allows for the introduction ofQ. Thus, generalized intermediate A9 is selectively deprotected toproduce alcohol A10, which in term is activated for displacement with Qby conversion to intermediate A11. A11 is reacted with Q to form thequaternary ammonium intermediate A12. Removal of any protecting groupsaffords the final product A13.

[0127] With reference to the flow sheets above, P, R¹, R, and M, are asdefined with respect to the compounds of formula I, except that M⁺ maybe a metal cation, e.g., Na⁺. See Dykstra, et al., Tet. Lett., 1998, 39,pg. 1865.

[0128] P** represents a carboxyl protecting group.

[0129] Many of compounds of the present invention are biologicallyactive against MRSA/MRCNS. In vitro antibacterial activity is predictiveof in vivo activity when the compounds are administered to a mammalinfected with a susceptible bacterial organism.

[0130] Using standard susceptibility tests, the compounds of theinvention are determined to be active against MRSA.

[0131] The compounds of the invention can be formulated inpharmaceutical compositions by combining the compound with apharmaceutically acceptable carrier. Examples of such carriers are setforth below.

[0132] The compounds may be employed in powder or crystalline form, inliquid solution, or in suspension. They may be administered by a varietyof means; those of principal interest include: topically, orally andparenterally by injection (intravenously or intramuscularly).

[0133] Compositions for injection, a preferred route of delivery, may beprepared in unit dosage form in ampules, or in multidose containers. Theinjectable compositions may take such forms as suspensions, solutions,or emulsions in oily or aqueous vehicles, and may contain variousformulating agents. Alternatively, the active ingredient may be inpowder (lyophillized or non-lyophillized) form for reconstitution at thetime of delivery with a suitable vehicle, such as sterile water. Ininjectable compositions, the carrier is typically comprised of sterilewater, saline or another injectable liquid, e.g., peanut oil forintramuscular injections. Also, various buffering agents, preservativesand the like can be included.

[0134] Topical applications may be formulated in carriers such ashydrophobic or hydrophilic bases to form ointments, creams, lotions, inaqueous, oleaginous or alcoholic liquids to form paints or in drydiluents to form powders.

[0135] Oral compositions may take such forms as tablets, capsules, oralsuspensions and oral solutions. The oral composions may utilize carrierssuch as conventional formulating agents, and may include sustainedrelease properties as well as rapid delivery forms.

[0136] The dosage to be administered depends to a large extent upon thecondition and size of the subject being treated, the route and frequencyof administration, the sensitivity of the pathogen to the particularcompound selected, the virulence of the infection and other factors.Such matters, however, are left to the routine discretion of thephysician according to principles of treatment well known in theantibacterial arts. Another factor influencing the precise dosageregimen, apart from the nature of the infection and peculiar identity ofthe individual being treated, is the molecular weight of the compound.

[0137] The compositions for human delivery per unit dosage, whetherliquid or solid, may contain from about 0.01% to as high as about 99% ofactive material, the preferred range being from about 10-60%. Thecomposition will generally contain from about 15 mg to about 2.5 g ofthe active ingredient; however, in general, it is preferable to employdosage amounts in the range of from about 250 mg to 1000 mg. Inparenteral administration, the unit dosage will typically include thepure compound in sterile water solution or in the form of a solublepowder intended for solution, which can be adjusted to neutral pH andisotonic.

[0138] The invention described herein also includes a method of treatinga bacterial infection in a mammal in need of such treatment comprisingadministering to said mammal a compound of formula I in an amounteffective to treat said infection.

[0139] The preferred methods of administration of the Formula Iantibacterial compounds include oral and parenteral, e.g., i.v.infusion, i.v. bolus and i.m. injection.

[0140] For adults, about 5-50 mg of Formula I antibacterial compound perkg of body weight given one to four times daily is preferred. Thepreferred dosage is 250 mg to 1000 mg of the antibacterial given one tofour times per day. More specifically, for mild infections a dose ofabout 250 mg two or three times daily is recommended. For moderateinfections against highly susceptible gram positive organisms a dose ofabout 500 mg three or four times daily is recommended. For severe,life-threatening infections against organisms at the upper limits ofsensitivity to the antibiotic, a dose of about 1000-2000 mg three tofour times daily may be recommended.

[0141] For children, a dose of about 5-25 mg/kg of body weight given 2,3, or 4 times per day is preferred; a dose of 10 mg/kg is typicallyrecommended.

[0142] The compounds of Formula I are of the broad class known ascarbapenems. Many carbapenems are susceptible to attack by a renalenzyme known as dehydropeptidase (DHP). This attack or degradation mayreduce the efficacy of the carbapenem antibacterial agent. Many of thecompounds of the present invention, on the other hand, are less subjectto such attack, and therefore may not require the use of a DHPinhibitor. However, such use is optional and contemplated to be part ofthe present invention. Inhibitors of DHP and their use with carbapenemsare disclosed in, e.g.,[European Patent Application Nos. 79102616.4,filed Jul. 24, 1979 (Patent No. 0 007 614); and 82107174.3, filed Aug.9, 1982 (Publication No. 0 072 014)].

[0143] The compounds of the present invention may, where DHP inhibitionis desired or necessary, be combined or used with the appropriate DHPinhibitor as described in the aforesaid patents and publishedapplication. The cited European Patent Applications define the procedurefor determining DHP susceptibility of the present carbapenems anddisclose suitable inhibitors, combination compositions and methods oftreatment. A preferred weight ratio of Formula I compound:DHP inhibitorin the combination compositions is about 1:1.

[0144] A preferred DHP inhibitor is7-(L-2-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclopropanecarboxamide)-2-heptenoicacid or a useful salt thereof.

[0145] The invention is further described in connection with thefollowing non-limiting examples.

PREPARATIVE EXAMPLE 1

[0146]

[0147] 500 mg (4.03 mmoles) of commercially available 4-hydroxybenzylalcohol was dissolved in 5.0 ml of anhydrous DMF, placed in an N₂atmosphere and chilled to 0° C. To the stirred DMF solution, 301 mg(4.33 mmoles) of imidazole was added followed by 604 mg (4.03 mmoles) oft-butyldimethylsilyl-chloride. The reaction was warmed to ambienttemperature and stirred for 18 hrs.

[0148] The reaction mixture was extracted with ethyl acetate andpartitioned with H₂O-dilute aq. sodium bicarbonate and sat. brine. Theethyl acetate extract was dried with anhydrous sodium sulfate andconcentrated in vacuo to provide a viscous oil.

[0149] The crude product was purified via flash chrom. (230-400 meshsilica gel) and was eluted with a 4:1 mixture of hexanes:ethyl acetateto afford 908 mg of the silyl ether.

[0150]¹H NMR (CDCl₃) δ: 0.10 (s, 6H), 0.94 (s, 9H), 4.66 (s, 2H), 6.08(s, 1H), 6.72 (d, J=7.5 Hz, 2H), 7.14 (d, J=8.7 Hz, 2H).

PREPARATIVE EXAMPLE 2

[0151]

[0152] 100 mg (0.418 mmoles) of the 4-hydroxy-silyl-ether was dissolvedin 2.0 ml of sieve dried dichloromethane and placed in an N₂ atmosphere.To the stirred dichloromethane solution, 109 mg (0.418 mmoles) ofthallium acetate was added and the tan suspension was stirred for 5 min.at ambient temperature. 109 mg (0.813 mmoles) of iodine was then added.The purple suspension was stirred for 2 hrs. and was filtered through acelite plug and was rinsed with 20 ml of ethyl acetate.

[0153] The ethyl acetate extract was partitioned with H₂O-ice and 5% aq.sodium thiosulfate and sat. brine. The extract was dried with andydroussodium sulfate and concentrated in vacuo to provide 108 mg of a tansolid.

[0154] The crude product was purified using plate layer chromatographywith a 4:1 hexanes:ethyl acetate eluent to provide 145 mg of theiodophenol.

[0155]¹H NMR (CDCl₃) δ: 0.07 (s, 6H), 0.90 (s, 9H), 4.60 (s, 2H), 5.18(s, 1H), 6.91 (d, J=8.3 Hz, 1H), 7.15 (dd, J=1.9 Hz, 6.3 Hz, 1H), 7.58(d, J=3.0 Hz, 1H).

PREPARATIVE EXAMPLE 3

[0156]

[0157] Using the analogous procedure of Preparative Example 1, the thecarbinol was converted to the silyl ether in yield.

[0158] Using the analogous procedure of Preparative Example 2, thephenol was converted to the iodophenol.

[0159]¹H NMR (CDCl₃) δ: 0.06 (s, 6H), 0.91 (s, 9H), 1.68 (m, 2H), 2.55(t, J=6.7 Hz, 2H), 3.58 (t, J=6.3 Hz, 2H), 5.22 (s, 1H), 6.88 (d, J=8.2Hz, 1H), 7.05 (dd, J=2.0 Hz, 6.3 Hz, 1H), 7.48 (d, J=2.0 Hz, 1H).

PREPARATIVE EXAMPLE 5

[0160]

[0161] Using the analogous procedure of Preparative Example 1, thecarbinol was converted to the silyl ether.

[0162]¹H NMR (CDCl₃) δ: 0.12 (s, 6H), 0.96 (s, 9H), 5.72 (s, 2H), 6.70(dd, J=1.9 Hz, 4.7 Hz, 1H), 6.83-6.88 (m, 2H), 7.16 (t, J=7.7 Hz, 1H).

PREPARATIVE EXAMPLE 6

[0163]

[0164] Using the analogous procedure of Preparative Example 2, thephenol was converted to the iodophenol.

[0165]¹H NMR (CDCl₃) δ: 0.10 (s, 6H), 0.94 (s, 9H), 4.66 (s, 2H), 5.29(s, 1H), 6.66 (dd, J=1.9 Hz, 4.7 Hz, 1H), 6.97 (d, J=2.0 Hz, 1H), 7.56(d, J=7.3 Hz, 1H).

PREPARATIVE EXAMPLE 7

[0166]

[0167] Using the analogous procedure of Preparative Example 1, thecarbinol was converted to the silyl ether.

[0168]¹H NMR (CDCl₃) δ: 0.08 (s, 6H), 0.88 (s, 9H), 2.76 (t, J=7.2 Hz,2H), 3.78 (t, J=7.2 Hz, 2H), 6.65-6.69 (m, 2H), 6.76 (d, J=7.4 Hz, 1H),7.12 (t, J=6.5 Hz, 1H).

PREPARATIVE EXAMPLE 8

[0169]

[0170] Using the analogous procedure of Preparative Example 2, thephenol was converted to the iodophenol.

[0171]¹H NMR (CDCl₃) δ: 0.10 (s, 6H), 0.88 (s, 9H), 2.72 (t, J=7.0 Hz,2H), 3.77 (t, J=6.9 Hz, 2H), 5.49 (s, 1H), 6.53 (dd, J=2.0 Hz, 6.1 Hz,1H), 6.89 (d, J=2.0 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H).

PREPARATIVE EXAMPLE 9

[0172]

[0173] 500 mg (1.712 mmoles) of the methyl ester (Stanley, W., M.;McMahan, E.; Adams, R. JACS, 1933, 55, 706) was dissolved in 2.9 ml of48% HBr and 1.49 ml of acetic acid and was placed in an N₂ atmosphere.The reaction was stirred for 4 hrs. at 120° C. The cooled reactionmixture was basified to pH 10.0 with 2 ml of 5N aq. sodium hydroxide andpartitioned with ethyl acetate-H₂O and ice. The aq. layer was saved andacidified to pH 2.5 with 2.0 N aq. hydrochloric acid, forming a whitesolid that precipitated from solution. The solid was collected in asintered glass funnel, washed with 10 ml of deionized H₂O and dried invacuo to provide 286 mg of benzoic acid.

[0174]¹H NMR (d₆-Me₂CO) δ: 7.06 (m, 1H), 7.29 (t, J=8.0 Hz, 1H), 7.51(dd, J=1.5 Hz, 5.9 Hz, 1H).

PREPARATIVE EXAMPLE 10

[0175]

[0176] 286 mg (1.08 mmoles0 of benzoic acid was dissolved in 5.0 ml ofanhydrous THF and was placed in an N₂ atmosphere. To the stirred THFsolution, 2.16 ml of borane-THF complex was added dropwise over 20 min.and the reaction was stirred for 2 hrs. at ambient temperature. 10 ml ofmethanol was then added to the THF solution slowly over 1 hr.

[0177] The reaction was extracted with ethyl acetate and partitionedwith H₂O-ice and sat. brine. The ethyl acetate extract was dried withanhydrous sodium sulfate and concentrated in vacuo to dryness. The crudeproduct was purified using silica gel plate layer chromatography elutedwith a 7:3 ethyl acetate:hexanes mixture to afford 120 mg of the benzylalcohol.

PREPARATIVE EXAMPLE 11

[0178]

[0179] Using the analogous procedure of Preparative example 1, thecarbinol was converted to the silyl ether.

[0180] 0.10 (s, 6H), 0.95 (s, 9H), 4.70 (s, 2H), 4.94 (s, 1H), 6.68 (dd,J=2.3 Hz, 5.5 Hz, 1H), 6.83 (m, 1H), 7.16 (t, J=7.8 Hz, 1H).

PREPARATIVE EXAMPLE 12

[0181]

[0182] To a stirred solution of commercially available2-(4-hydroxyphenyl)ethanol (3.0 g, 21.7 mmoles), in 30 ml of sieve driedN,N-dimethyformamide, at 0° C., was added imidazole (1.64 g, 23.9mmoles) followed by neat triethylsilyl triflate (5.4 ml, 23.9 mmoles).The resulting solution was warmed to ambient temperature and was stirredfor 18 hrs. The reaction mixture was diluted with ethyl acetate, washedwith cold 1.0N aq. HCl, conc. aq. sodium bicarbonate and sat. brine. Theorganic phase was dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to give a colorless oil. Flash chromatography(50:1 SiO₂:prod., eluent: 4:1 hexanes:ethyl acetate) gave 2.7 g (49%) ofa colorless oil.

[0183]¹H NMR (CDCl₃) δ: 0.62 (q, 6H), 0.95 (t, 9H), 2.82 (t, 2H), 3.80(t, 2H), 6.25 (s, 1H), 7.05 (d, 2H), 7.75 (d, 2H).

PREPARATIVE EXAMPLE 13

[0184]

[0185] To a stirred solution of (2.0 g, 7.91 mmoles) the productobtained in preparative example 12, in 30 ml of dichloromethane, atambient temperature, was added (2.08 g, 7.91 mmoles) of thallium (I)acetate in portions. After stirring the suspension for 5 min., iodine(4.0 g, 15.81 mmoles) was added and the mixture was stirred for 2.5 hrs.The resulting slurry was diluted with diethyl ether and filtered throughcelite. The filtrate was washed with water-ice, 5% aq. sodiumthiosulfate and sat. brine. The orgainic phase was dried over anhydroussodium sulfate and concentrated in vacuo to give a tan solid. Flashchromatography (100:1 SiO₂:product, eluent: 4:1 hexanes:ethyl acetate)gave 744 mg (27%) of the product as a crystalline solid; ¹H NMR (CDCl₃)δ: 0.08 (t, 9H), 2.75 (t, 2H), 3.75 (t, 2H), 5.25 (s, 1H), 7.18 (dd,1H), 7.52 (d, 1H) and 363 mg (17.4%) of the 4-hydroxethyl-2-iodophenol,shown below, as a tan solid; ¹H NMR (CDCl₃) δ: 2.78 (t, 2H), 3.76 (t,2H), 6.89 (d, 1H), 7.05 (dd, 1H), 7.55 (d, 1H).

PREPARATIVE EXAMPLE 14

[0186]

[0187] To a stirred solution of (121 mg, 0.458 mmoles) the4-hydroxethyl-2-iodophenol obtained in preparative example 13, in 2.0 mlof sieve dried N,N-dimethylformamide, at 0° C., was added imidazole (34mg, 0.504 mmoles) followed by neat trimethylsilyl chloride (0.057 ml,0.504 mmoles). The cooling bath was removed and the solution was stirredat ambient temperature for 18 hrs. The mixture was diluted with ethylacetate, washed with water, conc. aq. sodium bicarbonate and sat. brine.The organic phase was dried over anhydrous sodium sulfate andconcentrated in vacuo to provide 153 mg (100%) of a white crystallinesolid.

[0188]¹H NMR (CDCl₃) δ: 0.08 (t, 9H), 2.75 (t, 2H), 3.75 (t, 2H), 5.25(s, 1H), 7.18 (dd, 1H), 7.52 (d, 1H).

PREPARATIVE EXAMPLE 15

[0189]

[0190] To a stirred solution of commercially available propargyl alcohol(5.0 g, 35.72 mmoles) in 50 ml of sieve dried N,N-dimethylformamide,cooled to 0° C., was added imidazole (668 mg, 9.83 mmoles) followed byneat triethylsilyl chloride (16.2 ml, 96.21 mmoles). The cooling bathwas removed and the mixture was stirred at ambient temperature for 10min. The resulting solution was diluted with ethyl acetate, washed withwater-ice, 0.5M aq. sodium bicarbonate and saturated brine. The organicphase was dried over anhydrous sodium sulfate, filtered and concentratedin vacuo to give a colorless oil. Fractional distillation gave 3.03 g(51%) (b.p. 57° C.-61° C., 3.7 mm); of pure product as a colorless oil.

[0191]¹H NMR (CDCl₃) δ: 0.65 (q, 6H), 0.95 (t, 9H), 2.43 (t, 1H), 4.35(dd, 2H).

PREPARATIVE EXAMPLE 16

[0192]

[0193] To a stirred solution of product obtained in preparative example15 (3.03 g, 18.15 mmoles), in 30 ml of THF, cooled to −78° C., was addedn-butyllithium (8.0 ml, 19.96 mmoles) dropwise over 30 min. The reactionwas allowed to warmed to −20° C. and was stirred for 1 hour. Neattri-n-butyltin chloride (5.89 ml, 21.78 mmoles) was then added dropwiseover 30 min. The reaction mixture was warmed to 0° C. and stirred for 1hr. The resulting dark solution was diluted with ethyl acetate, washedwith water-ice and sat. brine. The organic phase was dried overanhydrous sodium sulfate, filtered and concentrated in vacuo to give abrown oil. Flash chromatography with 200-400 mesh florisil (100:1florisil:product, eluent: 9:1 hexanes:dichloromethane) gave 6.12 g (74%)of the product as a colorless oil.

[0194]¹ NMR (CDCl₃) δ: 0.64 (q, 6H), 0.91 (t, 6H), 1.02 (t, 18H), 1.31(m, 6H), 1.72 (m, 6H), 4.34 (s, 2H).

EXAMPLE 1

[0195]

[0196] To a stirred solution of carbapenem 2-yl-triflate 1 (100 mg,0.164 mmoles) and propargylstannane (112 mg, 0.246 mmoles) obtained inpreparative example 16, in 2 mL of anhydrous N,N-dimethylformamide, at0° C., was added lithium bromide (28 mg, 0.328 mmoles) andbis-acetonitrilepalladium (II) chloride (2.1 mg, 0.0082 mmoles). Thereaction mixture was stirred for 1 hr, diluted with ethyl acetate andwashed with water-ice and saturated brine. The organic phase was driedover anhydrous sodium sulfate, filtered and concentrated in vacuo togive an orange oil. Silica gel plate layer chromatography (2×1000microns; eluent: 4:1 hexane ethyl acetate) gave 70 mg (68%) of thedesired product as a pale yellow oil.

[0197]¹H NMR (CDCl₃) δ: 0.59 (m, 12H), 0.73 (m, 18H), 1.24 (d, 3H), 1.26(d, 3H), 3.18 (m, 1H), 3.20 (dd, 1H), 4.12 (d, 1H), 4.25 (dd, 1H), 4.53(s, 2H), 5.28-5.49 (q, 2H), 7.65 (d, 2H), 8.21 (d, 2H).

EXAMPLE 2

[0198]

[0199] To a stirred solution of (77 mg, 0.122 mmoles) the productobtained in example 1, in 1.0 ml of anhydrous THF, at 0° C., was addedsequentially acetic acid (11 ml, 0.183 mmoles) and a 1.0 M THF solutionof tetra-butylammonium fluoride (0.122 ml, 0.122 mmoles). The mixturewas stirred for 1 hr., diluted with ethyl acetate, washed with water,saturated aq. sodium bicarbonate and saturated brine. The organic phasewas dried over sodium sulfate, filtered and concentrated in vacuo togive a yellow solid. Silica gel plate layer chromatography (1×1000microns; eluent: 1:1 hexanes:ethyl acetate) gave 33 mg (53%) of a yellowcrystalline solid.

[0200] 1H NMR (CDCl₃) δ: 0.57 (q, 6H), 0.90 (t, 9H), 1.22 (t, 6H), 1.74(t, 1H), 3.16 (m, 1H), 3.23 (dd, 1H), 4.23-4.32 (m, 2H), 4.48 (d, 2H),5.26-5.48 (q, 2H), 7.64 (d, 2H), 8.21 (d, 2H).

EXAMPLE 3

[0201]

[0202] The product (82 mg, 0.159 mmoles) obtained from example 2 alongwith the product (58 mg, 0.179 mmoles) obtained in example 7 andtriphenylphosphine (46 mg, 0.179 mmoles) were combined, in 2.0 ml ofanhydrous THF and cooled to 0° C. Neat diisopropylazodicarboxylate(0.035 ml, 0.179 mmoles) was added and the mixture was stirred for 20min. The resulting solution was concentrated in vacuo to give an orangeoil. Silca gel plate layer chromatography (1×1000 microns; eluent: 4:1hexanes:ethyl acetate) gave 66 mg (56%) of a yellow oil.

[0203]¹H NMR (CDCl₃) δ: 0.1 (s, 9H), 0.63 (q, 6H), 0.89 (t, 9H), 1.14(d, 3H), 1.25 (d, 3H), 2.75 (m, 2H), 3.15 (m, 1H), 3.3 (m, 1H), 3.75 (t,2H), 4.25 (m, 2H), 4.91 (s, 2H), 5.35 (ABq, 2H), 6.95 (m, 1H), 7.15 (dd,1H), 7.62 (m, 3H), 8.21 (d, 2H).

EXAMPLE 4

[0204]

[0205] To a stirred solution of (66 mg, 0.0896 mmoles) the productobtained in example 3, in 1.0 ml of anhydrous THF, cooled to 0° C., wasadded sequentially acetic acid (0.0076 ml, 0.134 mmoles) and a 1.0 M THFsolution of tetra-butylammonium fluoride (0.089 ml, 0.089 mmoles). Themixture was stirred for 1 hr., diluted with ethyl acetate, washed withwater-ice, saturated aq. sodium bicarbonate and sat. brine. The organicphase was dried over anhydrous sodium sulfate, filtered and concentratedin vacuo to provide a colorless oil. Flash chrom. (50:1 SiO₂:product,eluent: 1:1 hexanes:ethyl acetate) gave 49 mg (72%) of a tan solid.

[0206]¹H NMR (CDCl₃) δ: 0.55 (q, 6H), 0.95 (t, 9H), 1.15 (d, 3H), 1.25(d, 3 H), 2.78 (t, 2H), 3.18 (m, 1H), 3.32 (dd, 1H), 3.85 (bt, 3H), 4.25(d, 1H), 4.28 (dd, 1H), 4.9 (s, 2H), 5.3 (ABq, 2H), 6.92 (d, 1H), 7.15(dd, 1H), 7.58 (d, 1H), 7.65 (dd, 1H), 8.18 (d, 1H).

EXAMPLE 5

[0207]

[0208] To a stirred solution of (49 mg, 0.0645 mmoles) the productobtained in example 4, in 1.0 ml of anhydrous THF, cooled to −20° C.,was added neat 2,6-lutidine (0.0079 ml, 0.0678 mmoles) and the solutionwas stirred for 5 min. Neat triflic anhydride (0.012 ml, 0.0710 mmoles)was then added and the mixture was stirred for 15 min. The reactionmixture was diluted with ethyl acetate, washed with water-ice, 0.050 mlof 2.0N aq. HCl and saturated brine. The organic phase was dried overanhydrous sodium sulfate, filtered and concentrated in vacuo to give 57mg (100%) of the desired product which was used without purification.

EXAMPLE 6

[0209]

[0210] To a stirred solution of (57 mg, 0.0645 mmoles) freshly preparedproduct obtained from example 5, in 1.0 ml of sieve dried acetonitrile,at ambient temperature, was added4-carbamoylmethyl-1,4-diazoniabicyclo-{2.2.2}-octyl triflate (21 mg,0.0645 mmoles). The solution was stirred for 30 min., concentrated invacuo to dryness and redissolved in 1.0 ml of acetone. The solution wasdiluted with 8.0 ml of diethyl ether to give a milky suspension whichwas centrifuged and dried to give 53 mg (76%) of a semi-pure amorphoussolid.

[0211]¹H NMR (CD₆CO) δ: 0.58 (q, 6H), 0.93 (t, 9H), 1.21 (m, 6H), 3.28(m, 1H), 3.35 (m, 2H), 3.58 (t, 1H), 4.02 (m, 2H), 4.20 (s, 2H), 4.31(m, 1H), 4.44 (dd, 1H), 4.47 (bt, 6H), 4.65 (s, 2H), 5.09 (s, 2H),5.29-5.47 (ABq, 2H), 7.11 (d, 2H), 7.29 (bs, 1H), 7.41 (dd, 1H), 7.72(bs, 1H), 7.78 (d, 2H), 7.82 (d, 1H), 8.21(d, 1H).

EXAMPLE 7

[0212]

[0213] To a stirred solution of (35 mg, 0.0292 mmoles) the productobtained in example 6, in a 2:1 mixture of THF:H₂O, cooled to 0° C., wasadded 1.0 N aq. HCl (0.029 ml, 0.029 mmoles). The cooling bath wasremoved and the reaction was stirred at ambient temperature for 1.5 hrs.The mixture was cooled to 0° C. and neutralized with 1.0N aq. sodiumbicarbonate (0.029 ml, 0.029 mmoles). 5% Pt/C (3.5 mg) catalyst was thenadded and the mixture was stirred vigorously, in an atmosphere ofhydrogen, at ambient temperature and pressure for 22 min. The reactionmixture was filtered through celite and concentrated in vacuo to give atan residue which was redissolved in 2.0 ml of deionized water. The aq.solution of crude product was passed through a column containing Macroprep ion exchange resin and was eluted with a 5% aq. brine solution andwas subsequently desalted using amberchrom CG-161 resin to give afterlyophilization 15.8 mg (79%) of a white solid.

[0214]¹H NMR (2:1 D₂O:CD₃CN) δ: 1.22 (d, 3H), 1.41 (d, 3H), 3.22 (m,3H), 3.56 (dd, 1H), 3.92 (m, 2H), 4.22 (bt, 6H), 4.34 (m, 2H) 4.44 (bt,6H), 4.60 (S, 2H), 5.25 (S, 2H), 7.34 (d, 1H), 7.53 (d, 1H), 8.05 (s,1H).

EXAMPLE 8

[0215]

[0216] Using the procedure described in example 3, a mixture of (70 mg,0.136 mmoles) the product obtained in example 2, 2-iodophenol (36 mg,0.163 mmoles) and triphenylphosphine (43 mg, 0.163 mmoles) is combinedand dissolved in 1.0 ml of anhydrous THF. The solution is cooled to 0°C., treated with diisopropylazodicarboxylate (0.032 ml, 0.163 mmoles)and stirred for 20 min. Purification by silica gel plate layerchromatography yields the product.

EXAMPLE 9

[0217]

[0218] Using the procedure described in example 7, the (82 mg, 0.114mmoles) product obtained in example 8, in 1.0 ml of a 2:1 THF:watersolution, is treated with 1.0 N aq. HCl (0.114 ml, 0.114 mmoles) andstirred at ambient temperature for 1.5 hrs. The resulting solution iscooled to 0° C. and basicified with 1.0N aq. sodium bicarbonate (0.228ml, 0.228 mmoles). Catalytic reduction using 5% Pt/C catalyst atatmospheric pressure in a hydrogen atmosphere followed by purificationwith amberchrom CG-161 resin gives after lyophilization the desiredproduct.

EXAMPLE 10

[0219]

[0220] A mixture of 2-yl-carbapenem triflate 1 (200 mg, 0.329 mmoles), a2:1 mixture of (E)-trans:(Z)-cis vinylstannanes (0.144 ml 0.493 mmoles),prepared as described in Jung, M. E.; Light, L. A. Tetrahedron Lett.1982, 23, 3851, palladium dibenzylidineacetone chloroform complex (17mg, 0.0165 mmoles) and tris-trifuryl phosphine (7.6 mg, 0.0329 mmoles)was combined and dissolved in 4.0 ml of N-methylpyrrolidinone, atambient temperature. A 1.0 M etheral solution of zinc chloride (0.0329ml, 0.0329 mmoles) was then added to the solution and the mixture wasstirred for 6 hrs. The mixture was diluted with ethyl acetate, washedwith water-ice and sat. brine. The organic phase was dried overanhydrous sodium sulfate, filtered and conc. in vacuo to give a brownoil. Silica gel plate layer chromatography (4×1000 microns, eluent: 1:1ethyl acetate:hexanes) yielded 103 mg (60%) of the desired product as acolorless oil.

[0221]¹H NMR (CDCl₃) δ: 0.58 (m, 6H), 0.94 (t, 9H), 1.22 (d, 3H), 1.29(d, 3H), 3.23 (dd, 1H), 3.37 (d, 1H), 4.19 (dd, 1H), 4.21 (m, 1H), 4.32(dd, 2H), 5.26-5.48 (q, 2H), 6.18 (dd, 1H), 7.27 (d, 1H), 7.68 (d, 2H),8.22 (d, 2H).

EXAMPLE 11

[0222]

[0223] Using the procedure described for example 3, the (113 mg, 0.218mmoles) product obtained in example 10 along with the (81 mg, 0.241mmoles) product obtained in example 7 and triphenylphosphine (63 mg,0.241 mmoles) is combined and dissolved in 2.0 ml of anhydrous THF. Thestirred solution is cooled to 0° C. and treated withdiisopropylazodicarboxylate (0.048 ml, 0.241 mmoles). Purification bysilca gel plate layer chromatography (1×1000 microns; eluent: 4:1hexanes:ethyl acetate) provides the product.

EXAMPLE 12

[0224]

[0225] Using the procedure described in example 4, the (91 mg, 0.123mmoles) product obtained in example 11, in 1.0 ml of anhydrous THF, istreated sequentially with acetic acid (0.0010 ml, 0.185 mmoles) and a1.0 M THF solution of tetra-butylammonium fluoride (0.136 ml, 0.136mmoles). Silica gel chromatography yields the depicted product.

EXAMPLE 13

[0226]

[0227] Using the procedure described in example 5, the (59 mg, 0.079mmoles) product obtained in example 13, in 1.0 ml of anhydrous THF, istreated with neat 2,6-lutidine (0.011 ml, 0.0931 mmoles) and neattriflic anhydride (0.016 ml, 0.0975 mmoles) to give the desired product.

EXAMPLE 14

[0228]

[0229] Using the procedure described in example 6, the (70 mg, 0.079mmoles) product obtained from example 13, in 1.0 ml of sieve driedacetonitrile, is reacted with4-carbamoylmethyl-1,4-diazoniabicyclo-{2.2.2}-octyl triflate (25 mg,0.079 mmoles). The desired product is precipitated from a solution ofacetone/ether to give the product.

EXAMPLE 15

[0230]

[0231] Using the procedure described in example 7, the (73 mg, 0.060mmoles) product obtained in example 14 in a 2:1 mixture of THF:H₂O,cooled to 0° C., is treated with 1.0N aq. HCl (0.060 ml, 0.060 mmoles)and stirred at ambient temperature for 1.5 hrs. The resulting solutionis cooled to 0° C. and basicified with 1.0N aq. sodium bicarbonate(0.060 ml, 0.060 mmoles). The mixture is catalytically hydrogenated with5% Pt/C (6.7 mg) catalyst to provide the crude residue which is treatedwith Macro prep ion exchange resin and is desalted with amberchromCG-161 resin to give after lyophilization 19 mg (44%) of the desiredproduct.

EXAMPLE 16

[0232]

[0233] Using the procedure described in example 3, a mixture of (57 mg,0.110 mmoles) the carbinol obtained in example 10, 2-iodophenol (29 mg,0.132 mmoles) and triphenylphosphine (35 mg, 0.132 mmoles) is combinedand dissolved in 1.0 ml of anhydrous THF. The stirred solution is cooledto 0° C. and treated with diisopropylazodicarboxylate (0.026 ml, 0.132mmoles). Silica gel plate layer chromatography yields the desiredproduct.

EXAMPLE 17

[0234]

[0235] Using the procedure described in example 7, the (59 mg, 0.081mmoles) product obtained in example 16, in 1.0 ml of a 2:1 THF:watersolution, is treated with 1.0N aq. HCl (0.081 ml, 0.081 mmoles) andstirred at ambient temperature for 1.5 hrs. The resulting solution iscooled to 0° C. and basicified with 1.0N aq. sodium bicarbonate (0.162ml, 0.162 mmoles). The mixture is catalytically hydrogenated using 5%Pt/C (5.9 mg) catalyst followed by purification with amberchrom CG-161resin to give after lyophiliztion the desired product.

What is claimed is:
 1. A compound represented by formula I:

or a pharmaceutically acceptable salt thereof, wherein: R¹ represents Hor methyl; CO₂M represents a carboxylic acid, a carboxylate anion, apharmaceutically acceptable ester group or a carboxylic acid protectedby a protecting group; X represents a halogen such as iodine, bromine,chlorine or fluorine; P represents hydrogen, hydroxyl, F or hydroxylprotected by a hydroxyl-protecting group; Z represents trans-ethenediylor ethynediyl; each R is independently selected from: —R*; —Q; hydrogen;halo; —CN; —NO₂; —NR^(a)R^(b); —OR^(c); —SR^(c); —C(O)NR^(a)R^(b);—C(O)OR^(h); —S(O)R^(c); —SO₂R^(c); —SO₂NR^(a)R^(b); —NR^(a)SO₂R^(b); —C(O)R^(a); —OC(O)R^(a); —OC(O)NR^(a)R^(b); —NR^(a)C(O)NR^(b)R^(c);—NR^(a)CO₂R^(h); —OCO₂R^(h); —NR^(a)C(O)R^(b); —C₁₋₆ straight- orbranched-chain alkyl, unsubstituted or substituted with one to fourR^(d) groups; and —C₃₋₇ cycloalkyl, unsubstituted or substituted withone to four R^(d) groups; each R^(a), R^(b) and R^(c) independentlyrepresents hydrogen, —R*, —C₁₋₆ straight- or branched-chain alkyl,unsubstituted or substituted with one to four R^(d) groups, or —C₃₋₇cycloalkyl, unsubstituted or substituted with one to four R^(d) groups;or R^(a) and R^(b) taken together with any intervening atoms represent a4-6 membered saturated ring optionally interrupted by one or more of O,S, NR^(c), with R^(c) as defined above, or —C(O)—, said ring beingunsubstituted or substituted with one to four R^(i) groups; or R^(b) andR^(c) taken together with any intervening atoms represent a 4-6 memberedsaturated ring optionally interrupted by one to three of O, S, NR^(a),with R^(a) as defined above, or —C(O)—, said ring being unsubstituted orsubstituted with one to four R^(i) groups; each R^(d) independentlyrepresents halo; —CN; —NO₂; —NR^(e)R^(f); —OR^(g); —SR^(g);—CONR^(e)R^(f); —COOR^(g); —SOR^(g); —SO₂R^(g); —SO₂NR^(e)R^(f);—NR^(e)SO₂R^(f); —COR^(e); —NR^(e)COR^(f); —OCOR^(e); —OCONR^(e)R^(f);—NR^(e)CONR^(f)R^(g); —NR^(e)CO₂R^(h); —OCO₂R^(h);—C(NR^(e))NR^(f)R^(g); —NR^(e)C(NH)NR^(f)R^(g); —NR^(e)C(NR^(f))R^(g);—R* or —Q; R^(e), R^(f) and R^(g) represent hydrogen; —R*; —C₁₋₆straight- or branched-chain alkyl, unsubstituted or substituted with oneto four R^(i) groups; or R^(e) and R^(f) taken together with anyintervening atoms represent a 4-6 membered saturated ring optionallyinterrupted by one to three of O, S, —C(O)— or NR^(g) with R^(g) asdefined above, said ring being unsubstituted or substituted with one tofour R^(i) groups; each R^(i) independently represents halo; —CN; —NO₂;phenyl; —NHSO₂R^(h); —OR^(h), —SR^(h); —N(R^(h))₂; —N⁺(R^(h))₃; —C(O)N(R^(h))₂; —SO₂N(R^(h))₂; heteroaryl; heteroarylium; —CO₂R^(h);—C(O)R^(h); —OCOR^(h); —NHCOR^(h); guanidinyl; carbamimidoyl or ureido;each R^(h) independently represents hydrogen, a —C₁₋₆ straight orbranched-chain alkyl group, a —C₃-C₆ cycloalkyl group or phenyl, or whentwo R^(h) groups are present, said R^(h) groups may be taken incombination and represent a 4-6 membered saturated ring, optionallyinterrupted by one or two of O, S, SO₂, —C(O)—, NH and NCH₃; Q isselected from the group consisting of:

wherein: a and b are 1, 2 or 3; L— is a pharmaceutically acceptablecounterion; α represents O, S or NR^(s); β, δ, λ, μ and σ representCR^(t), N or N⁺R^(s), provided that no more than one of β, δ, λ, μ and σis N⁺R^(s); R* is selected from the group consisting of:

wherein: d represents O, S or NR^(k); e, g, x, y and z represent CR^(m),N or N⁺R^(k), provided that no more than one of e, g, x, y and z in anygiven structure represents N⁺R^(k); R^(k) represents hydrogen; —C₁₋₆straight- or branched-chain alkyl, unsubstituted or substituted with oneto four R^(i) groups; or —(CH₂)_(n)Q where n=1, 2 or 3 and Q is aspreviously defined; each R^(m) independently represents a memberselected from the group consisting of: hydrogen; halo; —CN; —NO₂;—NR^(n)R^(o); —OR^(n); —SR^(n); —CONR^(n)R^(o); —COOR^(h); —SOR^(n);—SO₂R^(n); —SO₂NR^(n)R^(o); — NR^(n)SO₂R^(o); —COR^(n); —NR^(n)COR^(o);—OCOR^(n); —OCONR^(n)R^(o); —NR^(n)CO₂R^(h); —NR^(n)CONR^(o)R^(h);—OCO₂R^(h); —CNR^(n)NR^(o)R^(h); —NR^(n)CNHNR^(o)R^(h);—NR^(n)C(NR^(o))R^(h); — C₁₋₆ straight- or branched-chain alkyl,unsubstituted or substituted with one to four R^(i) groups; —C₃₋₇cycloalkyl, unsubstituted or substituted with one to four R^(i) groups;and —(CH₂)_(n)Q where n and Q are as defined above; R^(n) and R^(o)represent hydrogen, phenyl; —C₁₋₆ straight- or branched-chain alkylunsubstituted or substituted with one to four R^(i) groups; each R^(s)independently represents hydrogen; phenyl or —C₁₋₆ straight- orbranched-chain alkyl, unsubstituted or substituted with one to fourR^(i) groups; each R^(t) independently represents hydrogen; halo;phenyl; —CN; —NO₂; —NR^(u)R^(v); —OR^(u); —SR^(u); —CONR^(u)R^(v);—COOR^(h); —SOR^(u); —SO₂R^(u); —SO₂NR^(u)R^(v); —NR^(u)SO₂R^(v);—COR^(u); —NR^(u)COR^(v); —OCOR^(u); — OCONR^(u)R^(v); —NR^(u)CO₂R^(v);—NR^(u)CONR^(v)R^(w); —OCO₂R^(v); —C₁₋₆ straight- or branched-chainalkyl, unsubstituted or substituted with one to four R^(i) groups; R^(u)and R^(v) represent hydrogen or —C₁₋₆ straight- or branched-chain alkyl,unsubstituted or substituted with one to four R^(i) groups; or R^(u) andR^(v) together with any intervening atoms represent a 4-6 memberedsaturated ring optionally interrupted by one or more of O, S, NR^(w) or—C(O)—, said ring being unsubstituted or substituted with one to fourR^(i) groups; each R^(w) independently represents hydrogen; —C₁₋₆straight- or branched-chain alkyl, unsubstituted or substituted with oneto four R^(i) groups; C₃₋₆ cycloalkyl optionally substituted with one tofour R^(i) groups; phenyl optionally substituted with one to four R^(i)groups, or heteroaryl optionally substituted with 1-4 R^(i) groups; orR^(h) and R^(w) taken together with any intervening atoms represent a5-6 membered saturated ring, optionally interrupted by one or two of O,S, SO₂, NH or NCH₃; R^(x) represents hydrogen or a C₁₋₈ straight- orbranched-chain alkyl, optionally interrupted by one or two of O, S, SO,SO₂, NR^(w), N⁺R^(h)R^(w), or —C(O)—, said chain being unsubstituted orsubstituted with one to four of halo, CN, NO₂, OR^(w), SR^(w), SOR^(w),SO₂R^(w), NR^(h)R^(w), N⁺(R^(h))₂R^(w), —C(O)—R^(w), C(O)NR^(h)R^(w),SO₂NR^(h)R^(w), CO₂R^(w), OC(O)R^(w), OC(O)NR^(h)R^(w), NR^(h)C(O)R^(w),NR^(h)C(O)NR^(h)R^(w), or a phenyl or heteroaryl group which is in turnoptionally substituted with from one to four R^(i) groups or with one totwo C₁₋₃ straight- or branched-chain alkyl groups, said alkyl groupsbeing unsubstituted or substituted with one to four R^(i) groups; R^(y)and R^(z) represent hydrogen; phenyl; —C₁₋₆ straight or branched chainalkyl, unsubstituted or substituted with one to four R^(i) groups, andoptionally interrupted by O, S, NR^(w), N⁺R^(h)R^(w) or —C(O)—; or R^(x)and R^(y) together with any intervening atoms represent a 4-6 memberedsaturated ring optionally interrupted by O, S, SO₂, NR^(w) ,N⁺R^(h)R^(w) or —C(O)—, unsubstituted or substituted with 1-4 R^(i)groups, and when R^(x) and R^(y) together represent a 4-6 membered ringas defined above, R^(z) is as defined above or R^(z) represents anadditional saturated 4-6 membered ring fused to the ring represented byR^(x) and R^(y) taken together, optionally interrupted by O, S, NR^(w)or —C(O)—, said rings being unsubstituted or substituted with one tofour R^(i) groups.
 2. A compound in accordance with claim 1 wherein CO₂Mrepresents a carboxylate anion.
 3. A compound in accordance with claim 1wherein one R represents a group which contains a positively chargedmoiety, and the remaining R groups are selected from hydrogen and C₁₋₆straight or branched chain alkyl, unsubstituted or substituted with oneto four R^(d) groups.
 4. A compound in accordance with claim 3 whereinone R represents a group containing a positively charged moiety and theremaining R groups are hydrogen.
 5. A compound in accordance with claim1 wherein the R groups contain from 1-3 positive charges.
 6. A compoundin accordance with claim 5 wherein the R groups contain one positivecharge, balanced by a carboxylate anion and a negatively chargedcounterion.
 7. A compound in accordance with claim 1 wherein one R grouprepresents a —C₁₋₆ straight or branched chain alkyl group, substitutedwith one to four R^(d) groups, wherein one R^(d) group represents —R* orQ.
 8. A compound in accordance with claim 1 wherein Q is selected fromthe group consisting of:


9. A compound in accordance with claim 8 wherein wherein Q represents:

L—, a and b are as originally defined, and R^(x) represents a memberselected from the group consisting of: hydrogen or a C₁₋₈ straight- orbranched-chain alkyl, optionally interrupted or terminated by one or twoof O, S, SO, SO₂, NR^(w), N⁺R^(h)R^(w), or —C(O)—, said chain beingunsubstituted or substituted with one to four of halo, CN, NO₂, OR^(w),SR^(w), SOR^(w), SO₂R^(w), NR^(h)R^(w), N⁺(R^(h))₂R^(w), —C(O)—R^(w),C(O)NR^(h)R^(w), SO₂NR^(h)R^(w), CO₂R^(w), OC(O)R^(w), OC(O)NR^(h)R^(w),NR^(h)C(O)R^(w), NR^(h)C(O)NR^(h)R^(w), phenyl, or heteroaryl, saidphenyl and heteroaryl being optionally substituted with from one to fourR^(i) groups or with one to two C₁₋₃ straight- or branched-chain alkylgroups, said alkyl groups being unsubstituted or substituted with one tofour R^(i) groups, and R^(h), R^(i) and R^(w) are as originally defined.10. A compound in accordance with claim 1 wherein Q represents—N⁺R^(x)R^(y)R^(z), wherein R^(x), R^(y) and R^(z) are as originallydefined.
 11. A compound in accordance with claim 1 wherein one R* groupis present and is selected from:

d represents NR^(k); R^(k) represents —C₁₋₆ straight or branched chainalkyl; and e, g, x and y represent CR^(m) or N⁺R^(k), with R^(k) asdefined above and R^(m) representing hydrogen.
 12. A compound inaccordance with claim 1 wherein: CO₂M represents a carboxylate anion;one R group which is attached to the phenoxy platform contains at leastone positively charged moiety, and the remaining R groups are selectedfrom hydrogen and C₁₋₆ straight or branched chain alkyl, unsubstitutedor substituted with one to four R^(d) groups. R^(d) is as originallydefined; R^(h)represents hydrogen or a C₁₋₆ straight or branched chainalkyl group; Q is selected from the group consisting of:

wherein L— is as originally defined; a and b represent 2, and R^(x)represents a member selected from the group consisting of: hydrogen or aC₁₋₈ straight- or branched-chain alkyl, optionally interrupted orterminated by one or two of O, S, SO, SO₂, NR^(w), N⁺R^(h)R^(w), or—C(O)—, said chain being unsubstituted or substituted with one to fourof halo, CN, NO₂, OR^(w), SR^(w), SOR^(w), SO₂R^(w), NR^(h)R^(w),N⁺(R^(h))₂R^(w), —C(O)—R^(w), C(O)NR^(h)R^(w), SO₂NR^(h)R^(w), CO₂R^(w),OC(O)R^(w), OC(O)NR^(h)R^(w), NR^(h)C(O)R^(w), NR^(h)C(O)NR^(h)R^(w),phenyl, or heteroaryl, said phenyl and heteroaryl being optionallysubstituted with from one to four R^(i) groups or with one to two C₁₋₃straight- or branched-chain alkyl groups, said alkyl groups beingunsubstituted or substituted with one to four R^(i) groups; R* isselected from:

wherein d represents NR^(k); R^(k) represents —C₁₋₆ straight or branchedchain alkyl; and e, g, x and y represent CR^(m) or N⁺R^(k), with R^(k)as defined above and R^(m) representing hydrogen.
 13. A compound inaccordance with claim 1 wherein R is A—(CH₂)_(n)—Q, wherein A is O, S orCH₂ and n is 0-3 and Q is as originally defined.
 14. A compound inaccordance with claim 1 wherein Z is trans-CH═CH.
 15. A compound inaccordance with claim 1 wherein Z is C≡C.
 16. A compound in accordancewith claim 1 wherein X is iodine.
 17. A compound in accordance withclaim 1 represented by formula Ia:

wherein: Z is as originally described; CO₂M represents a carboxylateanion; R group contains a positively charged moiety; Rd is as originallydefined; R^(h) represents hydrogen or a C₁₋₆ straight or branched chainalkyl group; Q is selected from the group consisting of:

wherein L—, a and b are as originally defined, and R^(x) represents amember selected from the group consisting of: hydrogen or a C₁₋₈straight- or branched-chain alkyl, optionally interrupted or terminatedby one or two of O, S, SO, SO₂, NR^(w), N⁺R^(h)R^(w), or —C(O)—, saidchain being unsubstituted or substituted with one to four of halo, CN,NO₂, OR^(w), SR^(w), SOR^(w), SO₂R^(w), NR^(h)R^(w), N⁺(R^(h))₂R^(w),—C(O)—R^(w), C(O)NR^(h)R^(w), SO₂NR^(h)R^(w), CO₂R^(w), OC(O)R^(w),OC(O)NR^(h)R^(w), NR^(h)C(O)R^(w), NR^(h)C(O)NR^(h)R^(w), phenyl orheteroaryl, said phenyl or heteroaryl group being optionally substitutedwith from one to four R^(i) groups or with one to two C₁₋₃ straight- orbranched-chain alkyl groups, said alkyl groups being unsubstituted orsubstituted with one to four R^(i) groups; R* is selected from:

wherein d represents NR^(k); R^(k) represents —C₁₋₆ straight or branchedchain alkyl; and e, g, x and y represent CR^(m) or N⁺R^(k), with R^(k)as defined above and R^(m) representing hydrogen.
 18. A compound inaccordance with claim 17 wherein G is 1, 3-4, 6, 8, 9 or 10, R containsa positively charged moiety selected from the group consisting of: —R*,Q, A—(CH₂)_(n)—Q, and a C₁₋₆ straight or branched alkyl chainsubstituted with one R^(d) group, wherein A is O, S, CH₂ and n is 0-3;R^(d) is independently selected —R* or Q; Q is selected from the groupconsisting of:

wherein L—, a and b are as originally defined, and R^(x) represents amember selected from the group consisting of: hydrogen or a C₁₋₈straight- or branched-chain alkyl, optionally interrupted by one or twoof O, S, SO, SO₂, NR^(w), N⁺R^(h)R^(w), or —C(O)—, said chain beingunsubstituted or substituted with one to four of halo, CN, NO₂, OR^(w),SR^(w), SOR^(w), SO₂R^(w), NR^(h)R^(w), N⁺(R^(h))₂R^(w), —C(O)—R^(w),C(O)NR^(h)R^(w), SO₂NR^(h)R^(w), CO₂R^(w), OC(O)R^(w), OC(O)NR^(h)R^(w),NR^(h)C(O)R^(w), NR^(h)C(O)NR^(h)R^(w), phenyl or heteroaryl, saidphenyl and heteroaryl group being optionally substituted with from oneto four R^(i) groups or with one to two C₁₋₃ straight or branched chainalkyl groups, said alkyl groups being unsubstituted or substituted withone to four R^(i) groups; R* is selected from:

wherein d represents NR^(k); R^(k) represents —C₁₋₆ straight or branchedchain alkyl; and e, g, x and y represent CR^(m) or N⁺R^(k), with R^(k)as defined above and R^(m) representing hydrogen.
 19. A compoundaccording to claim 18 wherein G is 8 or
 9. 20. A compound according toclaim 1 represented by formula Ib:

or a pharmaceutically acceptable salt thereof, wherein: Z is asoriginally described and CO₂M represents a carboxylate anion.
 21. Acompound in accordance with claim 1 represented by formula Ic:

and R^(x), a, b and L— are as originally defined.
 22. A compound inaccordance with claim 1 wherein R represents A—(CH₂)_(n)—Q, wherein A isO, S or CH₂, n is 0-3 and Q is selected from the group consisting of:

wherein L—, a and b are as originally defined, and R^(x) represents amember selected from the group consisting of: hydrogen or a C₁₋₈straight- or branched-chain alkyl, optionally interrupted by one or twoof O, S, SO, SO₂, NR^(w), N⁺R^(h)R^(w), or —C(O)—, said chain beingunsubstituted or substituted with one to four of halo, CN, NO₂, OR^(w),SR^(w), SOR^(w), SO₂R^(w), NR^(h)R^(w), N⁺(R^(h))₂R^(w), —C(O)—R^(w),C(O)NR^(h)R^(w), SO₂NR^(h)R^(w), CO₂R^(w), OC(O)R^(w), OC(O)NR^(h)R^(w),NR^(h)C(O)R^(w), NR^(h)C(O)NR^(h)R^(w), phenyl or heteroaryl, saidphenyl and heteroaryl group being optionally substituted with from oneto four R^(i) groups or with one to two C₁₋₃ straight or branched chainalkyl groups, said alkyl groups being unsubstituted or substituted withone to four R^(i) groups.
 23. A compound which is:

or the pharmaceutically acceptable salts thereof.
 24. A pharmaceuticalcomposition comprised of a compound in accordance with claim 1 incombination with a pharmaceutically acceptable carrier.
 25. Apharmaceutical composition produced by combining a compound inaccordance with claim 1 with a pharmaceutically acceptable carrier. 26.A method of treating or preventing a bacterial infection in a mammalianpatient in need thereof, comprising administering to said patient aneffective amount of a compound of claim 1 .